Global Advisory Committee on Vaccine Safety, 9-10 June 2005

Published in the WER 15 July 2005

The Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body reporting to WHO, was established to deal with vaccine safety issues of potential global importance independently and with scientific rigour.1 GACVS held its twelfth meeting in Geneva, Switzerland, on 9–10 June 2005.2 The following issues, inter alia, were considered.

Mouse brain-derived Japanese encephalitis vaccine

The Committee considered the decision taken by the Government of Japan on 30 May 2005 to suspend routine vaccination with the mouse brain-derived Japanese encephalitis (JE) vaccine currently used in Japan.3 This decision followed a review by the Japanese national advisory committee on vaccine adverse events of a single case of acute disseminated encephalomyelitis following JE vaccination and the national committee’s conclusion that it could not rule out a causal link with the vaccine. GACVS was advised that there is no definite evidence of an increased risk of acute disseminated encephalomyelitis temporally associated with JE vaccine and a causal link has not been demonstrated. The national authority recommends vaccination in high-risk areas only and for travel to endemic regions. The Japanese Government expects that the national recommendation for vaccination will be reconsidered when newer, possibly safer, inactivated JE vaccines become available. GACVS concluded, on the information presently available, that there is no good reason for WHO and national immunization programmes to change the current recommendations for JE vaccination for residents in and travellers to JE-endemic regions. The Committee will review the situation if further information becomes available.

Safety of SA 14-14-2 Japanese encephalitis vaccine

GACVS considered recent data on the safety profile of live attenuated SA 14-14-2 JE vaccine, provided in a number of expert presentations to the Committee. Live attenuated SA 14-14-2 JE vaccine constitutes more than 50% of the global production of all JE vaccines. The anticipated global demand for JE vaccine in 2012 is expected to exceed the present requirement twofold. Even though several new vaccine candidates are in development, their production and distribution remain uncertain for the time being.

The current production of live attenuated SA 14-14-2 vaccine exceeds 50 million doses annually, most of which are used in China. Neuroattenuation of the virulent JE SA 14-14-2 strain is reported to be based on 57 nucleotide changes and 24 amino acid substitutions, suggesting that reversion to neurovirulence of the vaccine strain would be highly unlikely. Vaccine production is in accordance with WHO technical specifications, including detailed screening for adventitious viruses. Data reported from several studies have shown vaccine efficacy to be between 80% and 99% following single-dose vaccination and 98% or greater with 2 doses of the vaccine. In a comparative observational study of approximately 26 000 subjects in China undergoing routine immunization with JE vaccine, the most common reactions were fever, rash and vomiting. There was no increased risk of serious adverse events within 30 days of vaccination. Data presented to GACVS, covering a 20-year period from 1979 to 1998, contained no reported cases of vaccine-associated JE. Preliminary data on co-administration of the SA-14-14-2 JE vaccine with measles vaccine have been reassuring.

Information is available from both passive and active post-marketing surveillance in the Republic of Korea, where the SA 14-14-2 vaccine was first licensed in 2001. Of 522 vaccinated children actively monitored for adverse events for 4 weeks after vaccination, approximately 10% developed fever higher than 38 °C and a cough. Redness and swelling at the site of injection were observed in less than 1%. These findings are consistent with those reported from China.

GACVS took note of the work of the Program for Appropriate Technology in Health (PATH) – Japanese Encephalitis Project (JE Project), conducted in collaboration with WHO and other partners, in accelerating availability of a safe, effective and affordable JE vaccine in endemic countries in Asia. The SA 14-14-2 vaccine is especially important in this regard. GACVS noted that studies planned in collaboration with the PATH JE Project aim at addressing short- and long-term efficacy and safety, with special reference to co-administration with measles vaccine and evaluating the degree of viraemia in vaccinees.

GACVS acknowledged the excellent safety and efficacy profile of the SA 14-14-2 vaccine but nonetheless recommended more detailed study of the following: the safety profile in special risk groups including immunocompromised people and pregnant women; whether viral shedding occurs in vaccinees and the potential implications of such shedding; further analysis of sequential or co-administration of JE and measles vaccines; the interchangeability of inactivated and live JE vaccines; the safety of vaccine administration to infants aged under 1 year; and the implications for the efficacy and safety of the vaccine in infants with maternal antibodies against JE virus.

Isoniazid resistance of bacille Calmette–Guérin strains

The recent isolation of strains of bacille Calmette–Guérin (BCG) resistant to isoniazid from 5 patients with lymphadenitis in the Netherlands has brought into question the clinical relevance of the finding and whether the use of isoniazid-resistant BCG vaccine should be discontinued. The Netherlands experience relates to the Danish 1331 strain of BCG, used in the Netherlands since 1998. It is well known that there is a certain degree of isoniazid resistance of isolated BCG strains.

The use of isoniazid as single drug treatment for BCG vaccine-induced lymphadenitis is recommended only in the Netherlands. Elsewhere, most cases of BCG lymphadenitis are managed either by doing nothing or by surgical excision if necessary. For disseminated infection in patients with immune deficiency, treatment with 3 or more anti-tuberculosis drugs is recommended. A distinction should be made between such cases and those with lymphadenitis arising as a frequent consequence of BCG vaccination. Even in countries with a high prevalence of human immunodeficiency virus (HIV) infection in newborn infants, lymphadenitis is regarded as having no clinical relevance provided the correct injection technique has been used and adverse reactions are adequately treated. The Committee concluded that the isolation and identification of a low level of isoniazid resistance of BCG strains from 5 patients presenting with lymphadenitis do not justify a change in standard policy.

International drug monitoring

The Committee considered a presentation of the work of the Uppsala Monitoring Centre (UMC) in Sweden, a WHO Collaborating Centre for International Drug Monitoring, given by the Director of the UMC. Although the UMC had made much progress in analysing drug-related adverse events, there are limitations in the UMC programme with respect to vaccine-related reports. These limitations include the comparatively small number of and generally limited information in the reports reaching the UMC, difficulties inherent in dealing with signals using tools ¬developed to address non-vaccine drug-related issues, and the problems that have been experienced in communicating signals to national vaccine authorities.

GACVS proposed that WHO consider the need for improved monitoring and analysis of vaccine-related adverse events globally. The Committee suggested that WHO convene an in-depth consultation with a view to developing the current system further for detecting, reporting, analysing and communicating vaccine-related adverse events. The consultation would include international experts in drug safety, drug regulation and vaccine safety, including scientists from industry.

Thiomersal

The Committee considered a recently published pharmacokinetic study of thiomersal (contains ethyl mercury) in macaque monkeys.4 The systemic disposition and distribution in the brain of total and inorganic mercury were compared in infant monkeys following administration of thiomersal-containing vaccines and those exposed to methyl mercury. Differences between the kinetics of ethyl mercury and methyl mercury were examined. The findings confirmed the view that methyl mercury is not suitable for risk assessment of thiomersal. Brain concentrations of total mercury were threefold lower with thiomersal, compared with methyl mercury, and the average ratio of brain–blood concentrations of mercury was slightly higher for thiomersal-exposed infant monkeys. However, differences in primate and human brain development and species differences in the pharmacokinetics of mercury and mercury-containing compounds limit extrapolation of the results in these experimental conditions to what might be expected in human infants.

GACVS was informed of 2 neurodevelopmental studies currently being conducted in the United States and Italy of children who had received thiomersal-containing vaccines during infancy according to the national immunization schedules. Data analysis is presently in progress and the Committee will consider the results when they are available.

Currently, GACVS remains of the view that there is no evidence supporting a causal association between neurobehavioural disorders and thiomersal-containing vaccines.

Safety of hexavalent vaccines

In December 2004, GACVS reviewed the available data concerning a purported association between sudden unexplained death (SUD) and hexavalent diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, poliovirus and hepatitis B (DTaP-Hib-IPV-HepB) combination vaccines. The Committee concluded at that time that the evidence did not support a causal association between hexavalent vaccines and SUD, but recommended that additional studies be conducted to extend the observation period to the first 2 years of life.5

There have been no additional signals from Germany, where the first reports originated. The results from a population-based Italian study on sudden infant death (SID) and SUD cases in 5 birth cohorts (between 1999 and 2003) have produced no evidence of an increased risk of SID or SUD in the 48 hours following any immunization in the first year of life. Neither has any increased risk been observed related to the number of vaccine doses administered.

In Italy, between 1990 and 2001, infant mortality from any cause fell from 8.1 to 4.8 per 1000 births. Between 1991 and 2002, infant mortality from SID decreased in Germany, from 1.5 to 0.6 per 1000 births. This happened notwithstanding the introduction in the 2 countries of several new vaccines in the infant schedule, and increased immunization coverage in both countries.

GACVS concluded that these data are inconsistent with any association between hexavalent vaccines and SID or SUD.

Subacute sclerosing panencephalitis and measles vaccination

The WHO Regional Office for Europe requested GACVS to review the risk of measles vaccine strains causing subacute sclerosing panencephalitis (SSPE). The United States Institute of Medicine (IOM) statements in its 1994 and 2001 reviews refer to absent or inadequate evidence either to reject or accept any causal relationship between measles-containing vaccines and SSPE in immunocompetent individuals. It is uncertain whether there is enough evidence from viral RNA sequencing and classification to warrant any modification of the IOM conclusions. However, GACVS noted that: (i) all reports published since the IOM review in 2001 containing information on measles virus classification in SSPE-immunocompetent patients indicate the presence of wild (not vaccine) measles strains; and (ii) in countries where measles has been controlled, SSPE has either declined substantially or no longer occurs. These findings do not suggest an association between measles vaccines and SSPE. GACVS will commission a review of the epidemiology of SSPE in relation to measles vaccine, the results of which will be considered at its December 2005 meeting.

National regulatory authorities planning workshops

National regulatory authorities (NRAs) play a central role in assuring the quality, safety and efficacy of vaccines. However, in many developing countries NRAs do not meet these expectations. Since 1998, WHO has implemented a capacity-building programme to strengthen national vaccine regulatory systems. To date, 68 assessments of national vaccine regulatory systems have been conducted using a broad network of regulatory and vaccine experts. Of the 48 countries with vaccine-producing capacity, only 30 have a functional regulatory system. Moreover, many countries still have weak systems of post-marketing surveillance and remain dependent on external expertise to authorize clinical trials and evaluate new vaccines. To accelerate the assessment and capacity-building efforts in Africa, where many clinical trials of new vaccines are conducted, WHO has organized NRA planning workshops to evaluate the situation and encourage strengthening of the NRAs.

Efforts have also been made by WHO and the Pan American Health Organization to establish global and regional networks of regulatory authorities and regional groups of experts. The intention is to encourage countries to exchange information, share expertise and reach mutual recognition. Not all developing countries may need to build capacity in every aspect of vaccine regulation and may rely on expertise in a neighbouring country. Establishing such networks and groups should encourage official agreements, similar to those already existing in Europe and Asia, but will require a high level of political commitment from the countries concerned.

Modus operandi of the Committee

The scope of the Committee’s work and recent decisions, recommendations and actions, as well as its modus operandi, have been published in a recent issue of the American Journal of Public Health.6

1See No. 41, 1999, pp. 337-338

2GACVS invited additional experts to present evidence and participate in the discussions on mouse brain-derived Japanese encephalitis vaccine, safety of SA 14-14-2 Japanese encephalitis vaccine and thiomersal.